CF2H-synthon enables asymmetric radical difluoroalkylation for synthesis of chiral difluoromethylated amines
Abstract The difluoromethyl group is a crucial fluorinated moiety with distinctive biological properties, and the synthesis of chiral CF₂H-containing analogs has been recognized as a powerful strategy in drug design. To date, the most established method for accessing enantioenriched difluoromethyl c...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2025-01-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-55912-z |
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| author | Peng Liu Yan He Chen-Hui Jiang Wei-Ran Ren Ruo-Xing Jin Ting Zhang Wang-Xuan Chen Xuan Nie Xi-Sheng Wang |
| author_facet | Peng Liu Yan He Chen-Hui Jiang Wei-Ran Ren Ruo-Xing Jin Ting Zhang Wang-Xuan Chen Xuan Nie Xi-Sheng Wang |
| author_sort | Peng Liu |
| collection | DOAJ |
| description | Abstract The difluoromethyl group is a crucial fluorinated moiety with distinctive biological properties, and the synthesis of chiral CF₂H-containing analogs has been recognized as a powerful strategy in drug design. To date, the most established method for accessing enantioenriched difluoromethyl compounds involves the enantioselective functionalization of nucleophilic and electrophilic CF₂H synthons. However, this approach is limited by lower reactivity and reduced enantioselectivity. Leveraging the unique fluorine effect, we design and synthesize a radical CF₂H synthon by incorporating isoindolinone into alkyl halides for asymmetric radical transformation. Here, we report an efficient strategy for the asymmetric construction of carbon stereocenters featuring a difluoromethyl group via nickel-catalyzed Negishi cross-coupling. This approach demonstrates mild reaction conditions and excellent enantioselectivity. Given that optically pure difluoromethylated amines and isoindolinones are key structural motifs in bioactive compounds, this strategy offers a practical solution for the efficient synthesis of CF₂H-containing chiral drug-like molecules. |
| format | Article |
| id | doaj-art-dca3ff546f6a434590cb615b7d89e24a |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-dca3ff546f6a434590cb615b7d89e24a2025-01-12T12:31:21ZengNature PortfolioNature Communications2041-17232025-01-011611810.1038/s41467-025-55912-zCF2H-synthon enables asymmetric radical difluoroalkylation for synthesis of chiral difluoromethylated aminesPeng Liu0Yan He1Chen-Hui Jiang2Wei-Ran Ren3Ruo-Xing Jin4Ting Zhang5Wang-Xuan Chen6Xuan Nie7Xi-Sheng Wang8Department of Pharmacy, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of ChinaDepartment of Pharmacy, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of ChinaDepartment of Chemistry, University of Science and Technology of ChinaDepartment of Chemistry, University of Science and Technology of ChinaDepartment of Chemistry, University of Science and Technology of ChinaDepartment of Chemistry, University of Science and Technology of ChinaDepartment of Chemistry, University of Science and Technology of ChinaDepartment of Pharmacy, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of ChinaDepartment of Pharmacy, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of ChinaAbstract The difluoromethyl group is a crucial fluorinated moiety with distinctive biological properties, and the synthesis of chiral CF₂H-containing analogs has been recognized as a powerful strategy in drug design. To date, the most established method for accessing enantioenriched difluoromethyl compounds involves the enantioselective functionalization of nucleophilic and electrophilic CF₂H synthons. However, this approach is limited by lower reactivity and reduced enantioselectivity. Leveraging the unique fluorine effect, we design and synthesize a radical CF₂H synthon by incorporating isoindolinone into alkyl halides for asymmetric radical transformation. Here, we report an efficient strategy for the asymmetric construction of carbon stereocenters featuring a difluoromethyl group via nickel-catalyzed Negishi cross-coupling. This approach demonstrates mild reaction conditions and excellent enantioselectivity. Given that optically pure difluoromethylated amines and isoindolinones are key structural motifs in bioactive compounds, this strategy offers a practical solution for the efficient synthesis of CF₂H-containing chiral drug-like molecules.https://doi.org/10.1038/s41467-025-55912-z |
| spellingShingle | Peng Liu Yan He Chen-Hui Jiang Wei-Ran Ren Ruo-Xing Jin Ting Zhang Wang-Xuan Chen Xuan Nie Xi-Sheng Wang CF2H-synthon enables asymmetric radical difluoroalkylation for synthesis of chiral difluoromethylated amines Nature Communications |
| title | CF2H-synthon enables asymmetric radical difluoroalkylation for synthesis of chiral difluoromethylated amines |
| title_full | CF2H-synthon enables asymmetric radical difluoroalkylation for synthesis of chiral difluoromethylated amines |
| title_fullStr | CF2H-synthon enables asymmetric radical difluoroalkylation for synthesis of chiral difluoromethylated amines |
| title_full_unstemmed | CF2H-synthon enables asymmetric radical difluoroalkylation for synthesis of chiral difluoromethylated amines |
| title_short | CF2H-synthon enables asymmetric radical difluoroalkylation for synthesis of chiral difluoromethylated amines |
| title_sort | cf2h synthon enables asymmetric radical difluoroalkylation for synthesis of chiral difluoromethylated amines |
| url | https://doi.org/10.1038/s41467-025-55912-z |
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